The presentation of post-translationally modified (PTM) peptides by cell surface HLA molecules has the potential to increase the diversity of targets for surveilling T cells. Whilst immunopeptidomics studies routinely identify thousands of HLA-bound peptides from cell lines and tissue samples, in-depth analyses of the proportion and nature of peptides bearing one or more PTMs remains challenging. Here we have analyzed HLA-bound peptides from a variety of allotypes and assessed the distribution of mass spectrometry-detected PTMs, finding deamidation of asparagine or glutamine to be highly prevalent. Given that asparagine deamidation may arise either spontaneously or through enzymatic reaction, we assessed allele-specific and global motifs flanking the modified residues. Notably, we found that the N-linked glycosylation motif NX(S/T) was highly abundant across asparagine-deamidated HLA-bound peptides. This finding, demonstrated previously for a handful of deamidated T cell epitopes, implicates a more global role for the retrograde transport of nascently N-glycosylated polypeptides from the ER and their subsequent degradation within the cytosol to form HLA-ligand precursors. Chemical inhibition of Peptide:N-Glycanase (PNGase), the endoglycosidase responsible for the removal of glycans from misfolded and retrotranslocated glycoproteins, greatly reduced presentation of this subset of deamidated HLA-bound peptides. Importantly, there was no impact of PNGase inhibition on peptides not containing a consensus NX(S/T) motif. This indicates that a large proportion of HLA-I bound asparagine deamidated peptides are generated from formerly glycosylated proteins that have undergone deglycosylation via the ER-associated protein degradation (ERAD) pathway. The information herein will help train deamidation prediction models for HLA-peptide repertoires and aid in the design of novel T cell therapeutic targets derived from glycoprotein antigens.

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

Sodium glucose co-transporter-2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in diabetic patients. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK-mTOR and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction via regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and Sestrin2 knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight, whole-body fat, and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function, and reduced cardiac fat accumulation and mitochondria injury. Additionally, EMPA significantly augmented Sestrin2 levels, increased AMPK and eNOS phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed Sestrin2 knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1-mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.

A testosterone-lowering drug can reduce male pedophiles' risk of sexually abusing children, according to a new Swedish study.

Privacy isn't dead, but face surveillance technology might kill it, says civil rights advocate Kade Crockford. In an eye-opening talk, Kade outlines the startling reasons why this invasive technology -- powered by often-flawed facial recognition databases that track people without their knowledge -- poses unprecedented threats to your fundamental rights. Learn what can be done to ban government use before it's too late.

Social psychology -- Australia.

Australia -- History -- 1901-1945.

Paris : Steinheil, 1896.

Paris : O. Doin, 1879.

A Paris (rue St Jacques au dessus de celle des Mathurins au Gd. St. Remy : ches Huquier fils, graveur, [between 1700 and 1799]

São Paulo : Governo do Estado de Sao Paulo, Secretaria da Segurança Pública, 1975.

São Paulo : Serviço Grafíco da Secretaria da Segurança Pública, 1976.

São Paulo : Serviço Grafíco da Secretaria da Segurança Pública, 1976.

Rahul Mazumder, Haolei Weng.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1348--1385.

Abstract:
Estimating a low rank matrix from its linear measurements is a problem of central importance in contemporary statistical analysis. The choice of tuning parameters for estimators remains an important challenge from a theoretical and practical perspective. To this end, Stein’s Unbiased Risk Estimate (SURE) framework provides a well-grounded statistical framework for degrees of freedom estimation. In this paper, we use the SURE framework to obtain degrees of freedom estimates for a general class of spectral regularized matrix estimators—our results generalize beyond the class of estimators that have been studied thus far. To this end, we use a result due to Shapiro (2002) pertaining to the differentiability of symmetric matrix valued functions, developed in the context of semidefinite optimization algorithms. We rigorously verify the applicability of Stein’s Lemma towards the derivation of degrees of freedom estimates; and also present new techniques based on Gaussian convolution to estimate the degrees of freedom of a class of spectral estimators, for which Stein’s Lemma does not directly apply.

The USS Silversides is patrolling the Pacific during WWII when it finds itself in a terrifying situation: one of its torpedoes has jammed

The National Book Award winner's new book delves into matters of family grief and loss

Businesses in Cape Breton are helping customers get creative with DIY take-home kits to make everything from mermaid-themed terrariums to bubble tea.

“The timing couldn’t have been worse for refugees from Syria passing through Macedonia.” An OM worker shares about conditions in a Macedonian refugee transit camp.

A Bible study for the guardians of the pupils in Chiyembekezo School in Ntaja, Malawi, is bringing freedom to the women who attend.

Forty-seven women from all over the world are climbing Mt. Kilimanjaro in Kenya this week to raise awareness of global injustices against women and children.

The Freedom Climbers have completed the first leg of their trek up Mt. Kilimanjaro. They climb to raise awareness and funds to combat slavery.

After five days of strenuous hiking and altitude sickness, the Freedom Climbers rejoice at the summit of Mt. Kilimanjaro, fittingly called Uhuru (freedom) Peak.

150 gathered for the first Freedom Climb Conference in September to learn how to become advocates for oppressed women and children around the world.

The Freedom Climb team completes the first few days of the journey to Mt. Everest Base Came and Kala Patthar Peak. Please pray for them.

The Freedom Climbers remain encouraged through increasing altitudes and dropping temperatures as they continue upward to Mt. Everest Base Camp and Kala Patthar Peak.

The Freedom Climb team has made it safely back to Kathmandu, and each climber is heading home.

The Freedom Climb becomes The Freedom Challenge to include more women in a movement to raise awareness, prayer and funds to combat slavery.

Forty women climb Machu Picchu to raise awareness about human trafficking during a five-day Freedom Challenge trek in Peru.

On 1 December, 22 women hiked Tongariro Alpine Crossing to raise awareness and funds for women and children trafficked in France and India.

About 110 men, women and children climbed five volcanoes in Auckland in the Freedom Climb New Zealand on Saturday, 16 August.

Balboa, Panama :: Crewmembers teach sewing skills to young mothers from a local tribe and donate sewing machines to the community.

At the heart of missions lies a passion for justice. In every community in which OM is involved, working for justice for the oppressed and vulnerable is part of ministry.

With the vision to raise the next generation of national leaders, OM Cambodia runs a children’s home and youth live-in centre in Phnom Penh.

Lots of companies do business in foreign countries, even Communist countries, but Google is getting singled out for its China plans as if it could bring down PRC all by itself.

Newborn infants who are predominantly breastfed are much more likely to develop prolonged hyperbilirubinemia than those fed formula, but the prevalence of prolonged hyperbilirubinemia in a largely white, North American, breastfed population is unknown.

Practitioners can be reassured that it is normal for 20% to 30% of predominantly breastfed infants to be jaundiced at age 3 to 4 weeks and for 30% to 40% of these infants to have bilirubin levels ≥5 mg/dL. (Read the full article)

• National team and staff raise money for health service

A French man met in the street prefered to live without God, thinking He would take away his freedom.

CNA Staff, May 1, 2020 / 12:09 pm (CNA).- The Turkish foreign ministry on Wednesday rejected Turkey's inclusion in a report by the US Commission on International Religious Freedom, charging that the report comes from a “biased mindset”.

“The report contains baseless, unaccredited and vague allegations as in the past years while trying to portray isolated incidents as violations of religious freedoms through far-fetched accusations,” Hami Aksoy, a spokesperson for the Turkish Ministry of Foreign Affairs, said April 29.

“The importance attached by Turkey to protect religious freedoms, including those of religious minorities, is expressed at the highest level by our Government officials. Our authorities make it clear that any harm to the religious freedoms of our citizens will not be tolerated,” Aksoy added.

In its 2020 report, USCIRF recommended that the State Department add Turkey, as well as 10 other countries, to a “Special Watch List” of countries where abuses of religious minorities are taking place, but not at a level as severe as in those designated as “countries of particular concern.”

The commission wrote that “religious freedom conditions in Turkey remained worrisome” in 2019, “with the perpetuation of restrictive and intrusive governmental policies on religious practice and a marked increase in incidents of vandalism and societal violence against religious minorities.”

It cited the Turkish government's prevention of the election of board members for non-Muslim religious groups and its limitations on the election of the Armenian Patriarch of Constantinople.

The report added that Alevis, a group related to Shia Islam and the country's largest religious minority, “remained unable to gain official recognition for their gathering houses (cemevleri) as places of worship or to exempt their children from compulsory religious classes, despite European Court of Human Rights (ECtHR) rulings finding that these policies violated Alevis’ rights.”

According to the US commission, Turkish religious minorities “expressed concerns that governmental rhetoric and policies contributed to an increasingly hostile environment and implicitly encouraged acts of societal aggression and violence.”

The report also drew attention to the permission given for a museum, that was originally a Greek Orthodox church and later a mosque, to be reconverted into a mosque. It noted also that president Recep Tayyip Erdoğan has called for the same thing to happen to the Hagia Sophia, which has the same history.

USCIRF also said the Turkish government has “continued to dismiss, detain, and arrest individuals affiliated with, or accused of affiliation with, the U.S.-based cleric Fethullah Gülen, for alleged complicity in a July 2016 coup attempt or involvement in terrorist activity.”

Gülen has lived in the US since 1999, and is considered a terrorist by the Turkish government.

The Turkish foreign ministry charged that Gülen's mention in the report “amounts to deliberately turning a blind eye” to the coup attempt, and added: “We invite the US authorities to earnestly examine the evidence we have provided” about the Gülen movement “and to engage in effective cooperation in line with the spirit of alliance in order to reveal the true nature of this terrorist organization.”

Aksoy added that the recommendation of adding Turkey to a “special watch list” for religious freedom “is a clear indication of the biased mindset behind it and the circles under whose influence it was drawn up.”

“In the report that is supposed to include global trends that threaten religious freedoms, the Commission does not mention a single word about xenophobia, Islamophobia and discrimination on religious grounds that is on the rise in the West and the US,” Aksoy stated.

“This clearly reveals that the purpose of the report is not to protect religious rights and freedoms. It is clear that the Commission, which has been accused of being anti-Muslim in the past, has drawn up this report based on its unwarranted agenda and priorities under the influence of circles that are hostile to Turkey, rather than objective criteria. We recommend the authors of this report to look in the mirror and engage in self-criticism.”

Earlier this year, Turkish authorities arrested a Syriac Orthodox priest on terrorism charges after he provided bread and water to members of a Kurdish separatist group that has been deemed illegal.

Gildelia Moromisato is starting a Freedom Climb initiative in Brazil after attending the annual conference of the OM ministry focused on oppressed women and children.

Brazil’s mission training programme provides practical experience and cross-cultural knowledge for participants heading overseas.

Antofagasta, Chile :: Logos Hope crewmembers tell men who've battled with addiction and crime about Jesus' love for them.

When/Where: Saturday, July 7th, 2018 @ 9:00am (Rain or Shine). Registration starts at 8am. Silver Lake Park, Dover, DE                               (Use Washington Street entrance off of State Street) We’re back and ready for all our great supporters to register for our annual ‘Freedom 5K!’ It’s not too late to convince your family and friends to come help […]

Activities to include demonstrations by the First Delaware Regiment and "Caesar Rodney in his Own Words," a historical play exploring the views of the famed Delaware patriot.